Oral eniluracil/5-FU for advanced colon and breast carcinomas

Abstract

5-fluorouracil (5-FU) is irreversibly catabolized to dihydrofluorouracil, an inactive metabolite, by the enzyme dihydropyrimidine dehydrogenase (DPD). This catabolic pathway is a critical step in determining 5-FU availability for conversion to nucleotides and eventual incorporation into either RNA or DNA. Inactivation of DPD, therefore, is an approach to enhance the availability of 5-FU for potential improved therapeutic effect. Preclinical animal and human studies have demonstrated that eniluracil is an effective inactivator of DPD. Phase I studies have been completed showing the tolerability of two dosing schedules, including (1) a chronic schedule with twice-daily administration of eniluracil plus oral fluorouracil (5-FU) (10:1 ratio) for 28 days, and (2) a schedule of eniluracil administered daily on days 1-7 with oral 5-FU once daily on days 2-6. The phase I trials have demonstrated limited toxicities including diarrhea, mucositis, and neutropenia. Follow-up clinical trials have targeted colon and breast cancers in particular.